JPH07599B2 - New derivative of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde oxime, process for producing the same and drug containing the same - Google Patents

Abstract

Compounds useful in the treatment of Alzheimer's disease, senile dementia, or memory disorders which have the formula <IMAGE> in which R represents a hydrogen atom, a linear, branched or cyclic alkyl radical, saturated or unsaturated, containing up to 8 carbon atoms, possibly substituted by a free or esterified carboxy radical or R represents an aralkyl radical containing up to 10 carbon atoms and R' represents a linear or branched, saturated or unsaturated, alkyl radical, containing up to 8 carbon atoms, a radical -COalk1 or a radical -(CH2)2N(alk2)2, alk1 and alk2 representing an alkyl radical containing up to 8 carbon atoms, as well as their addition salts with acids. Also compositions containing the same, method of preparation and method of treatment using the same.

Description

Description: TECHNICAL FIELD OF THE INVENTION The present invention relates to a novel derivative of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde oxime, a process for producing the same, its use as a drug and its use. To the composition.

[Prior art and its problems]

Derivatives of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde oxime, such as 1,2,5,6-tetrahydropyridine-3-carboxaldehyde [Chem.Ber. 40 , 4685 , 1907], or 1-methyl-1,2,
5,6-Tetrahydropyridine-3-carboxaldehyde oxime (Chem. Ber. 40 , 4712, 1907), and 1-ethyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde oxime (Chem. Ber. 38 , 4161, 1905], that is, the following general formula Compounds corresponding to are already known.

Some of these compounds have been studied in the field of pharmacology [Journal of Pharmacy Sci. (Vol.56, J.Pharm.Sci.)].
1190, 1967), but their efficacy was judged to be very weak, and they were much less active than arecoline.

Here, it is unexpectedly found that certain compounds with similar chemical structure exhibit very superior and beneficial pharmacological properties over arecoline, as shown by the results of the pharmacological tests described below. Was found.

[Specific Description of the Invention]

The subject of the invention is the following formula (I) [Wherein R is a hydrogen atom, a saturated or unsaturated linear, branched or cyclic alkyl group containing up to 8 carbon atoms, which is substituted by a free or esterified carboxyl group Or R is an aralkyl group containing up to 10 carbon atoms and R'is a saturated or unsaturated linear or branched alkyl group containing up to 8 carbon atoms. , Or --COalk ₁ or-(CH ₂ ) ₂ N (alk ₂ ) ₂ groups (wherein alk ₁ and alk ₂ represent alkyl groups containing up to 8 carbon atoms) In acid addition salt.

Examples of acid addition salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, and citric acid. It may be a salt formed with an acid, silicic acid, glyoxylic acid, aspartic acid, an alkanesulfonic acid such as methane or ethanesulfonic acid and an arylsulfonic acid such as benzene or p-toluenesulfonic acid.

When R or R'represents a saturated linear or branched alkyl group, methyl, ethyl, n-propyl, isopropyl,
N-butyl, sec-butyl, isobutyl, n-pentyl, n-hexyl, t-butyl, t-pentyl, neopentyl or n-hexyl groups are preferred.

When R or R'represents an unsaturated alkyl group, it is an ethylenic group such as vinyl, allyl, 1,1-dimethylallyl or 2-butenyl group; or acetylene such as ethynyl or propynyl group. Groups of the system are preferred.

When R represents a cyclic alkyl group, cyclopropyl,
Cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl groups are preferred.

When R represents an aralkyl group, a benzyl or phenethyl group is preferred.

When R represents an alkyl group substituted with an esterified carboxyl group, it is an alkoxycarbonyl group, the alkoxy group of which contains up to 8 carbon atoms (eg methoxy, ethoxy, linear or branched). It is preferably a group substituted by propoxy, or a linear or branched broxy group).

Alk ₁ and Alk ₂ preferably represent methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or isobutyl groups.

More particularly, the invention is directed to compounds of formula (I) in which R represents a hydrogen atom and their acid addition salts.

The invention also relates, in particular, to compounds of the formula (I) in which R represents a saturated or unsaturated alkyl radical containing 1 to 4 carbon atoms, in particular a methyl, ethyl, propyl or allyl radical, and their acids. The subject is addition salts.

Among the preferred compounds of the present invention, there may be mentioned the compounds of formula (I) in which R'represents a methyl group and their acid addition salts.

More specifically, the invention relates to compounds whose preparation is detailed in the experimental part. Among these, preferred compounds include the compounds of Examples 1, 3, 7, 8 and 10.

The compounds of the invention have very valuable pharmacological properties, especially
It shows a large choline-like activity and a long duration of activity by oral administration.

It is well known that learning and memory difficulties in the elderly are associated with dysfunction of the central cholinergic system, especially senile dementia and Alzheimer's disease.

Therefore, it is clear that drugs with central cholinergic action can be used for the treatment of these diseases (Bartus, Science 217 , 408, 1982).

Also, intravenously injected arecoline has been shown to have a positive effect on patients with amnesia (Citaram et al., Science 201 , 274, 1978; Christie et al., Brit.JP.
sychiatry 138 , 46, 1981).

However, the limiting therapeutic use of arecoline is associated with the fact that this substance has a very weak activity upon oral administration and a short duration of action.

The compounds of formula (I), which are the subject of the present invention, showed a central choline-like activity which was 1500 times higher than that of arecoline and a very long duration of action after oral administration.

Accordingly, the present invention resides in compounds of formula (I) as agents useful in the treatment of Alzheimer's disease or senile dementia and memory disorders.

Among the agents of the present invention, especially Examples 1, 3, 7, 8 and 10
Compounds.

The effective dose may vary depending on the disease, the patient and the route of administration, but is 1 mg to 100 mg / day, for example 1 to 15 mg / day by the oral administration of the compound of Example 3 or more.

The present invention is also directed to pharmaceutical compositions containing as active ingredient at least one compound of formula (I).

The pharmaceutical compositions of the present invention may be solid or liquid and may be provided in the pharmaceutical forms normally used in human medicine, such as tablets or dragees, capsules, granules, suppositories, injectable formulations. They are manufactured by the usual methods. The active ingredient is an adjuvant commonly used in these pharmaceutical compositions,
For example in talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and / or preservatives. Can be blended with.

The present invention is also directed to a process for preparing a compound of formula (I), which process comprises the following formula (II) (Wherein R has the same meaning as defined above) or one of its salts is represented by the following formula (III) NH ₂ OR ′ ₁ (III) (wherein R ′ ₁ is a hydrogen atom or up to 8) Represents a saturated or unsaturated linear or branched alkyl group containing a carbon atom of), or by reacting one of its salts with the corresponding formula (I _A ) Or a salt of this compound is formed, or
Or R ′ ₁ represents a hydrogen atom, the following formula (IV) R ′ ₂ Hal (IV) [wherein R ′ ₂ is —COalk ₁ or — (CH ₂ ) ₂ N- (alk ₂ ) ₂ group (here in alk ₁ and alk ₂ represent an have) defined above, the following formula Hal corresponds by the action of a compound of a halogen atom] (I _B) To give the compound, then the following formula (VI) R ₁ Hal optionally if R in the compound or compounds of formula (I _B) of the formula where R _'1 does not represent a hydrogen atom (I _A) represents a hydrogen atom (VI) [wherein Hal represents a halogen atom, R ₁ is a saturated or unsaturated linear, branched or cyclic alkyl group containing up to 8 carbon atoms (which is an esterified carboxyl group; May be substituted) or R ₁ is
Representing an aralkyl group containing up to 10 carbon atoms] by reacting a compound of the formula (I _C ) A compound of the formula (I) in which R ₁ and R ′ have the meanings given above, is salted if necessary, or R ₁ represents an esterified carboxyl group. _It is characterized in that the compound of _C ) is reacted with a hydrolyzing agent to obtain a corresponding compound having a free carboxyl group, and this compound is subjected to salt formation if necessary.

According to a preferred embodiment for carrying out the above-mentioned production method of the present invention, the compound of formula (II) and the compound of formula (III) are used in the form of hydrochloride.

It is a chlorine or bromine atom of Hal in the compounds of the formulas R ′ ₂ Hal and R ₁ Hal.

The hydrolyzing agent is p-toluene sulfonate.

The present invention is also directed to a modification of the above-mentioned manufacturing method, which is represented by the following formula (V) (Wherein R'has the previously given meaning) a compound of formula (VI) as described above is allowed to act on a compound of formula (VII) Of the compound of formula (I _C ) (Wherein R ₁ and R ′ have the meanings given above), salting this compound if desired or alkyl substituted with a carboxyl group on which R ₁ is esterified When it represents a group, it is characterized by reacting with a hydrolyzing agent to obtain a corresponding compound having a free carboxyl group, and if desired, salting this compound.

According to a preferred embodiment of the above production method, the hydrogenating agent used is sodium borohydride and the hydrolyzing agent is p-toluenesulfonic acid.

The compound of formula (II) is a generally known compound, and can be produced by the method described in Chem. Ber. 40 , 4685, 1907.

Compounds of formula (I _A) in which R _'1 represents a hydrogen atom an alien with known compounds, Chem.Ber. 40, it is possible to follow connexion manufacturing to the method described in 4712,1907.

The compound of the formula (V) is also a generally known compound, and is a compound of the journal heterocycle chemistry (J.
Het.Chem) 1979, 1459.

〔Example〕

The following examples illustrate the invention but do not limit it in any way.

Example 1 1-Methyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime hydrochloride 1.42 g (0.017 mol) of 1-methyl in a solution of 2.74 g (0.017 mol) of 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde hydrochloride in 10 cc of water Add hydroxylamine hydrochloride and stir at ambient temperature for 2 hours. The solvent is evaporated, the residue is taken up with acetone, the product is filtered and recrystallized from absolute ethanol. Yield 1.
75g (54%), white crystalline powder, mp = 228 ° C (decomposition).

Analysis: C ₈ H ₁₄ N ₂ O.HCl (MW190.681) Found: C% 50.57 H% 7.94 N% 14.56 Calculated: 50.39 7.93 14.69 Water, 2N HCl, 95 ° ethanol, soluble in chloroform, and 2N NaOH, It is soluble in benzene, ethyl ether and acetone.

Example 2 1-Methyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-ethyloxime hydrochloride 4g of (0.025 mol) of 1-methyl-1,2,5,6-tetrahydropyridin-3-carboxaldehyde hydrochloride (Chem.Ber. 4
0 , 4712, 1907) in a solution of 15cc water 2.42g
(0.025 mol) O-ethylhydroxylamine hydrochloride is added, the mixture is stirred at ambient temperature for 1 hour, then evaporated to dryness and the residue crystallized from absolute ethanol. Yield 3.1 g (60.6%), mp = 197 ° C (decomposition).

Decomposition: C ₉ H ₁₆ N ₂ O.HCl (MW204.708) Measurement: C% 52.61 H% 8.47 N% 13.47 Calculation: 52.80 8.37 13.68 Water, 2NHCl, 95 ° Soluble in ethanol, slightly soluble in chloroform. It is soluble and insoluble in 2N NaOH, ethyl ether, acetone.

Example 3 1,2,5,6-Tetrahydropyridine-3-carboxaldehyde-O-methyloxime hydrochloride 5 g (0.034 mol) of 1,2,5,6-tetrahydropyridine-3-
Carboxaldehyde hydrochloride (Chem. Ber. 40 , 4685, 190
2.85 g (0.034 mol) of O-methylhydroxylamine hydrochloride is added to a solution prepared by dissolving 7) in 30 cc of water and stirred at ambient temperature for 1 hour. The reaction mixture was evaporated to dryness,
The residue is recrystallized from absolute ethanol. 4.8g (80%)
The expected compound was obtained. mp = 208 ° C (decomposition). White crystalline powder.

Analysis: C ₇ H ₁₂ N ₂ C ₉ CL (MW176.654) Found: C% 47.42 H% 7.38 N% 15.63 Calculated: 47.59 7.42 15.86 Water, 2NHCl, 2N NaOH, soluble in 95 ° ethanol and benzene, Insoluble in ethyl ether, acetone and chloroform.

Example 4 O-isopropyl-N-methyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde oxime hydrochloride 0.86 g (0.0077 mol) of O-isopropyl in a solution of 1.24 g (0.0077 mol) of 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde hydrochloride in 10 cc of water Add hydroxylamine hydrochloride to 1 at ambient temperature
Stir the time. Then the solvent is evaporated and the residue is recrystallized from absolute ethanol. Yield 1 g (59.4%), white crystalline powder, mp = 234 ° C (decomposition).

Analysis: C ₁₀ H ₁₈ N ₂ OHCl (MW218.735) Measurement: C% 55.04 H% 8.84 N% 12.73 Calculation: 54.91 8.75 12.81 Water, 2NHCl, 95 ° Soluble in ethanol, slightly soluble in chloroform Yes, it is insoluble in 2NaOH, benzene, ethyl ether and acetone.

Example 5 1-Methyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-acetyloxime 2g of (0.0142 mol) of 1-methyl-1,2,5,6-tetrahydropyridin-3-carboxaldehyde oxime (Chem.Ber. 4
0 , 4712, 1907) was dissolved in 20 cc of anhydrous tetrahydrofuran, and 1.44 g (0.0142 mol) of triethylamine and 1.12 g (0.0142 mol) of acetyl chloride were added,
Stir for 1 hour at ambient temperature. The reaction mixture is treated with water and then with aqueous sodium bicarbonate solution, the organic phase is separated off,
Dry and evaporate the solvent. The residue was distilled at 0.05 mmHg to collect the fraction with bp = 170-175 ° C. Yield 2.1g (81%).
It is a yellow oil which darkens over time without showing any sign of conversion to the solid state (SS).

Treatment with HCl-ether gives the hydrochloride, which partially hydrolyzes.

Analysis: C ₉ H ₁₄ N ₂ O ₂ Found: C% 59.54 H% 7.72 N% 15.45 Calculation: 59.32 7.74 15.37 Soluble in water, 2N HCl, 2N NaOH, 95 ° ethanol, benzene, ethyl ether, acetone and chloroform.

Example 6 3- [2- (N, N-dimethylaminoethoxyimino) methyl]
-1-methyl-1,2,5,6-tetrahydropyridine 2g of (0.0142 mol) of 1-methyl-1,2,5,6-tetrahydropyridin-3-carboxaldehyde oxime (Chem.Ber. 4
0 , 4712, 1907) and 2.06 g (0.0143 mol) of β-dimethylaminoethyl chloride hydrochloride were obtained by dissolving 0.66 g (0.0287 mol) of sodium in 40 cc of absolute ethanol. ]] The mixture is heated to boiling point for 2 hours, then cooled and the solution evaporated. The residue is taken up with a little 2N NaOH to remove the starting oxime still present and extracted with ethyl acetate. The organic phase was separated, dried, the solvent was evaporated and the residue was distilled at 0.02 mmHg to collect a fraction with bp = 100-105 ° C.
Yellow liquid, yield 2.3g (76%).

Analysis: C ₁₁ H ₂₁ N ₃ O.HCl (MW211.312) Measurement: C% 62.21 H% 9.84 N% 19.84 Calculation: 62.52 10.01 19.88 Water, 2N HCl, 95 ° Ethanol, benzene, ethyl ether, acetone and chloroform Melted, and 2N
Slightly soluble in NaOH.

Example 7 1-Ethyl-1,2,5,6-tetrahydro-3-carboxaldehyde-O-methyloxime hydrochloride Step A 1-Ethyl-3- (methoxyiminomethyl) pyridine iodide 10.6 g (0.078 mol) of 3-pyridinecarboxamide-O-methyl oxime [J. Het. Chem. (1979), 1459] and 12 g (0.
A solution of 077 mol of iodoethane dissolved in 100 cc of acetone is heated to boiling point for 5 hours. 7.8g (0.05
(Mol) iodoethane is added and heated at boiling point for a further 4 hours. The reaction mixture is cooled and the solvent is evaporated. The residue is an oil which solidifies on cooling.

Yield 16g (70.2%), mp = 118 ° C (decomposition).

It is used in the next reaction without further purification.

Step B 1-Ethyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime hydrochloride To a solution prepared by dissolving 10 g (0.034 mol) of 1-ethyl-3- (methoxyiminomethyl) pyridine iodide in 100 cc of anhydrous methanol, keeping the temperature at 20-22 ° C in an ice bath,
Add 2.5 g (0.066 mol) sodium borohydride. When the addition is complete, continue stirring for 1 hour at ambient temperature, then evaporate the solvent and dissolve the residue with 2N HCl.
It is made alkaline with solid sodium bicarbonate and then extracted with ethyl acetate. The oily residue is taken up with ethyl ether and filtered over activated charcoal. The solution is sparged with HCl gas, filtered over the separating hydrochloride salt and recrystallized from absolute ethanol. Yield 1.5g (21.5%), white crystalline powder, mp = 220 ℃
(Disassembly).

Analysis: C ₉ H ₁₆ N ₂ O.HCl (MW204.708) Measurement: C% 52.65 H% 8.34 N% 13.42 Calculation: 52.80 8.37 13.68 Water, 2NHCl, 95 ° ethanol, soluble in chloroform, 2N NaOH, benzene , Insoluble in ethyl ether and acetone.

Example 8 1-Propyl-1,2,5,6-tetrahydropyridine-2-carboxaldehyde-O-methyloxime (hydrochloride) 1.5 g (0.0085 mol) of 1,2,5,6-tetrahydropyridine-
1.74 g (0.017 mol) of triethylamine and 1.05 g of 3-carboxaldehyde-O-methyloxime (see Preparation 1) in 15 cc of dimethylformamide
Add (0.0085 mol) 1-bromopropane. The reaction mixture is heated at 70 ° C. for 2 hours, then cooled and evaporated to dryness. Combine the residue with water and solid sodium bicarbonate,
Then extract with ethyl acetate. The organic phase is separated, dried and the solvent evaporated. The residue is silica gel (particle size 0.04
˜0.063 mm) column and elute with acetone-ethyl ether mixture (1: 1). Evaporation of the eluent leaves an oil which is treated with ethereal HCl. The hydrochloride salt separates out and is recrystallized from absolute ethanol. Yield 0.9g (48.4%), white crystalline powder, mp = 220 ° C (decomposition).

Analysis: C ₁₀ H ₁₅ N ₂ O.HCl Actual: C% 55.04 H% 8.91 N% 12.74 Calculation: 54.91 8.75 12.81 Example 9 1-Butyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde- O-methyl oxime (hydrochloride) 1.1 g (0.0062 mol) of 1,2,5,6-tetrahydropyridine-
1.26 g (0.0124 mol) of triethylamine and 0.85 g (0.0062 mol) of 1-bromobutane in a mixture of 3-carboxaldehyde-O-methyloxime hydrochloride (see Preparation 1) dissolved in 15 cc of anhydrous dimethylformamide. And stir at ambient temperature for 2 hours. After evaporation to dryness, the residue is combined with water and anhydrous potassium carbonate and then extracted with ethyl acetate. The organic phase is separated, dried and the solvent evaporated. The residue is chromatographed on a silica gel column, eluting with a mixture of chloroform and ethanol (7: 3). The eluent was evaporated, the residue was combined with dry HCl in anhydrous ether, filtered over with hydrochloric acid and dehydrated in absolute ethanol-
Recrystallize from anhydrous ethyl ether. Yield 0.85g (59
%), White crystalline powder, mp = 186 ° C. (decomposition).
(A change in the crystal form was observed at 175 ° C with the Kofler meter, and melting occurs at 195 ° C.) Analysis: C ₁₁ H ₂₀ N ₂ O.HCl Actual measurement: C% 56.61 H% 8.93 N% 11.92 Calculation: 56.76 9.09 12.04 Example 10 1-allyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime (hydrochloride) 1.2 g (0.0068 mol) of 1,2,5,6-tetrahydropyridine-
A solution of 3-carboxaldehyde-O-methyloxime (see Preparation 1) in 15 cc of anhydrous dimethylformamide was added with 1.38 g (0.01136 mol) of triethylamine and 0.
Add 825 g (0.068 mol) of freshly distilled allyl bromide. The reaction mixture is stirred for 2 hours at ambient temperature and then evaporated to dryness. Combine the residue with water and potassium carbonate,
Then extract with ethyl acetate. The organic phase is separated, dried and the solvent evaporated. The residue is dissolved in anhydrous ether, filtered over activated charcoal and treated with HCl gas. Pass the hydrochloride salt that separates and recrystallize from absolute ethanol.

Yield 1.2g (81.4%), white crystalline powder, mp = 220
° C (decomposition). The analytical sample is recrystallized from absolute ethanol. mp = 221 ° C (decomposition).

Analysis: C ₁₀ H ₁₆ N ₂ O.HCl (MW190.681) Found: C% 55.02 H% 7.72 N% 12.74 Calculation: 55.42 7.91 12.93 Example 11 1-Pentyl-1,2,5,6-tetrahydropyridine-3 -Carboxaldehyde-O-methyl oxime (hydrochloride) 1.5 g (0.0085 mol) of 1,2,5,6-tetrahydropyridine-
A mixture of 3-carboxaldehyde-O-methyloxime hydrochloride (see Preparation 1) dissolved in 20 cc of dimethylformamide was added with 1.72 g (0.017 mol) of triethylamine.
Add 1.28 g (0.0085 mol) of 1-bromopentane and stir the whole at ambient temperature for 3 hours. The solvent is evaporated to dryness, the residue is taken up with a little water and extracted with ethyl acetate. The organic phase is separated, dried and the solvent evaporated. The residue is dissolved with anhydrous ethyl ether and the solution is treated with gaseous HCl. The hydrochloride salt which separates is recrystallized from a mixture of absolute ethanol and anhydrous ethyl ether.

Yield 1.1g (52.4%), white crystalline powder, mp = 18
5 ℃ (decomposition). The mp remains unchanged after further crystallization with the same solvent mixture. The change in crystal form is 14
It is observed at 0 ° C and melts completely at 191 ° C.

Analysis: C ₁₂ H ₂₂ N ₂ O.HCl (MW190.681) Found: C% 58.27 H% 9.48 N% 11.19 Calculated: 58.40 9.39 11.35 Soluble in water and 2N HCl and insoluble in 2N NaOH.

Example 12 1-Methyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-propargyl oxime (hydrochloride) 1.84 g of 1-methyl-1,2,5,6-tetrahydropyridine-3-
1.23 g (0.00114 mol) of O-propargyl hydroxylamine hydrochloride (HC≡CCH ₂ ONH ₂ .HCl; U.S. Pat. No. 3,39) was added to a solution of carboxaldehyde hydrochloride dissolved in 15 cc of water.
(Described in No. 8,180) and stir at ambient temperature for 1 hour. The reaction mixture is evaporated to dryness and the residue is crystallized from absolute ethanol.

Yield 2.2g (about 90%). White crystalline powder, mp = 15
7 ° C (decomposition).

Analysis: C ₁₀ H ₁₄ N ₂ O.HCl (MW190.681) Found: C% 55.81 H% 6.95 N% 13.11 Calculation: 55.94 7.04 13.05 Soluble in water, 2N HCl and 2N NaOH.

Example 13 1-Benzyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime Step A 1-Benzyl-3-carboxaldehyde-O-methyloxime pyridinium bromide 22 g of 3-ald Xime pyridine-O-methyl ether (JH
et.Chem.1979, p.1459) dissolved in absolute ethanol.
0.2 g of benzyl bromide are added and the whole is heated to reflux for 12 hours. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of ethanol and anhydrous ether, and after passing, 39.5 g of the desired compound was obtained. mp = 103-106 ° C.

Step B 1-Benzyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyl oxime (hydrochloride) The product obtained above 30 g was dissolved in 250 cc of anhydrous methanol to give Cool to 10 ° C, keeping the temperature at 5-10 ° C 4.
8 g sodium borohydride are added in small portions. The mixture is stirred for 2 hours at ambient temperature and then the solvent is removed under reduced pressure at 40 ° C. The residue was chromatographed on silica eluting with a mixture of ethyl acetate and toluene (6-4) to give 13 g of the product in the base form. bp = 230 ℃ / 0.05mmH
g. This was converted to the hydrochloride salt. Mp = 261 ° C. after recrystallization from 95% ethanol (decomposition).

Analysis: C ₁₄ H ₁₈ N ₂ O.HCl (MW266.775) Calculation: C% 63.03 H% 7.18 N% 10.50 Measurement: 62.88 7.31 10.24 Example 14 1-Cyclopropylmethyl-1,2,5,6-tetrahydropyridine -3-Carboxaldehyde-O-methyloxime (hydrochloride) Add 0.9 g of chloromethylcyclopropane to 2.8 g of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime, After heating for 3 hours, 0.45 g of chloromethylcyclopropane is added and the temperature is kept at 80 ° C for 6 hours. The mixture is then cooled, diluted with anhydrous ethyl ether and passed. Chromatograph the liquid on silica,
Elute with ethyl acetate. After removing the solvent, 0.1 at 130 ℃
1.4 g of an oil are obtained which is distilled at mmHg, which is then acidified by bubbling gaseous hydrochloric acid into anhydrous ethyl ether and crystallized from a mixture of ethanol and ethyl ether. mp
= 233 ° C (decomposition).

Analysis: C ₁₁ H ₁₈ N ₂ O.HCl (MW230.745) Calculation: C% 57.25 H% 8.30 N% 12.14 Measurement: 57.03 8.17 11.96 Production 1 1,2,5,6-tetrahydropyridine used as starting material
Preparation of 3-carboxaldehyde-O-methyloxime Step A: 1-α-chloroethoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime 13.2 g of 1-benzyl -1,2,5,6-tetrahydropyridine-3
-Carboxaldehyde-O-methyloxime dissolved in 120 cc of anhydrous 1,2-dichloroethane is cooled to 0 ° C, 11.7 g of α-chloroethyl chloroformate is added, and the whole is heated under reflux for 2 hours. . After cooling, pass the insoluble matter,
The liquid is evaporated to dryness, the residue is taken up with anhydrous ether, diluted and passed. The liquid is evaporated to give 19.8 g of product, which is used immediately in the next reaction.

Step B: 1,2,5,6-Tetrahydropyridine-3-carboxaldehyde-O-methyloxime 19 g of the product obtained above are dissolved in 100 cc of anhydrous methanol and heated to 50 ° C. for 1 hour. Evaporate the solvent to dryness, dissolve the residue in anhydrous ethyl ether, stir, pass, and 8.
4 g of the expected compound is obtained.

Example 15 1,1-Dimethylethoxycarbonylmethyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime hydrochloride 4.5 g of 1,2,5,6-tetrahydropyridine-3- Carboxaldehyde-O-methyl oxime (prepared as in Example 14) is dissolved in 30 cc of anhydrous benzene. 3.25 g of triethylamine are added, then 6.3 g of T-butyl bromoacetate are added gently. After reacting for 30 minutes, triethylamine chloride formed was passed over, benzene was evaporated, and the residue was removed.
Distillation at 130 ° C. and 1 mmHg gave 6 g of oily product. The hydrochloride is made with gaseous hydrochloric acid in anhydrous ethyl ether and recrystallized from a mixture of ethanol and anhydrous ether.

mp = 182 ° C (decomposition).

Analysis: C ₁₃ H ₂₂ N ₂ O ₃ .HCl (MW290.797) Calculation: C% 53.69 H% 7.97 N% 9.63 Measurement: 53.87 8.03 9.81 Example 16 1-Carboxymethyl-1,2,5,6-tetrahydropyridine -
3-carboxaldehyde-O-methoxyimino hydrochloride 3 g of 1- (1,1-dimethylethoxycarbonylmethyl) -1,
Dissolve 2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime in 30 cc of anhydrous toluene, 2.
27 g of p-toluenesulfonic acid are added and the whole is heated under reflux for 1 hour. After evaporation to dryness, the residue is taken up with 1,2-dichloroethane, salted with gaseous hydrochloric acid and precipitated with anhydrous ethyl ether. After filtration and recrystallization from ethanol, 1.8 g of the expected compound was obtained. mp = 213 ° C (decomposition).

Analysis: C ₉ H ₁₄ N ₂ O ₃ .HCl (MW234.692) Calculation: C% 46.06 H% 6.44 N% 11.94 Found: 45.92 6.27 11.91 Example 17 1- (2-butenyl) -1,2,5,6 -Tetrahydropyridine-3-
Carboxaldehyde-O-methyloxime hydrochloride carried out as in Example 15 with crotyl bromide in dimethylformamide with stirring at ambient temperature. The dry residue is taken up with a little water and extracted with ethyl acetate. The resulting hydrochloride salt has a melting point (decomposition) of 215 ° C.

Analysis: C ₁₁ H ₁₈ N ₂ O.HCl (MW230.745) Calculation: C% 57.26 H% 7.86 N% 12.14 Measurement: 57.02 8.06 12.07 Example 18 1- (2-Propyl) -1,2,5,6- Tetrahydropyridine-3-
Carboxaldehyde-O-methyloxime hydrochloride 3.2 g of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime are heated to reflux with 1.41 g of 2-bromopropane for 1 hour. After alkalinizing with 10% aqueous potassium carbonate, extract with ethyl acetate and evaporate the extract to dryness. The residue is chromatographed on silica, eluting with a mixture of methanol and chloroform (2-8). 1.2 g of oil are obtained which is distilled at 110 ° C. and 0.08 mm Hg, then acidified with gaseous hydrochloric acid in ether.
After recrystallization from an isopropyl alcohol-ethyl ether mixture, the hydrochloride salt with mp = 210 ° C. (decomposition) was obtained.

Analysis: C ₁₀ H ₁₈ N ₂ O.HCl (MW218.728) Calculation: C% 54.91 H% 8.76 N% 12.81 Measurement: 54.68 8.72 12.71 Example 19 1- (2-propynyl) -1,2,5,6- Tetrahydropyridine
3-Carboxaldehyde-O-Methyloxime Hydrochloride Performed as in Example 17 with propynyl bromide to give the desired hydrochloride salt. mp = 229 ° C (decomposition).

Analysis: C ₁₀ H ₁₄ N ₂ O.HCl (MW214.696) Calculation: C% 55.94 H% 7.04 N% 13.05 Found: 56.02 7.07 12.88 Example 20 1-Cyclopentyl-1,2,5,6-tetrahydropyridine-3 -
Carboxaldehyde-O-Methyloxime Hydrochloride Performed as in Example 18 with cyclopentyl bromide and heated at 60 ° C. for 8 hours to give the desired compound. mp = 213 ° C.

Analysis: C ₁₂ H ₂₀ N ₂ O.HCl: 244.766 Calculation: C% 58.89 H% 8.65 N% 11.45 Found: 58.62 8.49 11.38 Example 21 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O- Propargyl oxime hydrochloride 1.47 g 1,2,5,6-tetrahydropyridine-3-carboxaldehyde hydrochloride (Chem. Ber. 40 , 4685, 1907) and 1.07 g O-propargyl hydroxylamine hydrochloride (US Patent (No. 3,398,180)
Carried out more as in Example 12. 12 g of the expected compound is obtained. mp = 202 ° C.

Analysis: C ₉ H ₁₂ N ₂ O.HCl (MW200.676) Calculation: C% 53.87 H% 6.5 N% 14.12 Found: 53.64 6.53 13.96 Example 22 1-Methyl-1,2,5,6-tetrahydropyridine-3 -Carboxaldehyde-O-allyl oxime hydrochloride To a solution of 0.5 g of sodium dissolved in 20 cc of absolute ethanol, 2.7 g of N-methyl-1,2,5,6-tetrahydropyridine-3-aldoxime (J .Pharm.Science ces 56 (9), 11
90, 1967), followed by 1.67 cc of allyl bromide. The mixture is heated at reflux for 3 hours, then poured into 60 cc of water and extracted with methylene chloride. The organic phase is washed with brine, dried and concentrated. Chromatograph the residue on silica to a mixture of ethyl acetate and methanol (95-5).
Elute with. 1 g of oil was obtained which distilled at 125-130 ° C at 5 mm Hg. This oil is dissolved in anhydrous ether and salted with gaseous hydrochloric acid. The hydrochloride obtained is recrystallized from a mixture of methanol and ethyl ether. mp = 168-169 ℃
(Disassembly).

Analysis: C ₁₀ H ₁₆ N ₂ O.HCl (MW216.712) Calculation: C% 55.42 H% 7.91 N% 12.93 Found: 55.14 7.82 12.76 Example 23 1-Methyl-1,2,5,6-tetrahydropyridine-3 -Carboxaldehyde-O-buten-2-yloxime hydrochloride starting from 3.5 cc of crotyl bromide and 3.8 g of 1-methyl-1,2,5,6-tetrahydropyridine-3-aldoxime and heating at reflux for 4 hours And carried out as in Example 22. 160-165
1.78 g of oil was obtained which distilled at 3 mmHg at ° C. Then mp
= 164-165 ° C (decomposition) hydrochloride salt was produced.

Analysis: C ₁₁ H ₁₈ N ₂ O.HCl (MW230.739) Calculation: C% 57.26 H% 8.30 N% 12.14 Measurement: 54.04 8.28 11.99 Pharmacological study 1. Acute toxicity 16 hours fasted 22-24g body weight A male rat (CD ₁ Charles Rivers species) was used. Test compound is 1000mg, 500m
Oral doses of g, 250 mg, 125 mg, 62 mg, 31 mg and 16 mg / Kg were administered. The mortality rate for 7 days after treatment was checked. The following LD ₅₀ was obtained. Compound, Example No.LD ₅₀ , mg / Kg 1 450 2 250 3 75 4 350 5 500 6 750 8 100 9 30 10 175 11 175 12 60 Arecoline HBr 600 2. Guinea pig ileal contraction test Killed by decapitation The ileum part was excised from the guinea pig. The isolated ileum was thermostated at 37 ° C and treated with O ₂ (95%).
10 ml of Tyrode (Tyrod) aerated with a mixture of CO ₂ (5%)
e) Suspended in the bath containing the solution. The contracting effect of the test compound was detected using an Isomeric Transducer connected to a recorder. Test compounds range from 1 × 10 ^-3 to 1 × 10 ^-8
Was added at a scalar concentration between.

It was proved whether the test compound endowed with the contractile activity was in the muscarinic type or the nicotine type in comparison with atropine or hexamethonium. The potential antagonist activity of the test compounds was also tested in contrast to acetylcholine.

Agonist activity was expressed as pD ₂ (negative log of dose producing 50% of maximal effect).

Antagonistic activity was expressed as ED ₅₀ (the dose that abrogates 50% of the maximal response induced by acetylcholine).

The following results were obtained.

3. Study of diarrhea activity Male rats (CD ₁ CHARLES RIVERS) having a body weight of 25 to 30 g and fasted for 6 hours were used. The test compound was dissolved in methylcellulose at a concentration of 0.5% and orally administered using an esophageal probe. For the control, only vehicle (20 mg / Kg) was given.

After treatment, the animals were placed separately in cages whose bottoms were covered with blotter paper and observed for 30, 60, 120 and 180 minutes after treatment. The absorbent paper sheet was changed after each observation. Randall Barth's Method (Arch.Int.Pharmadyn. 220 , 94, 1976)
The fecal consistency is optionally assessed according to the following scale.

0: Solid consistency 1: Moderately soft feces with or without dampness 2: Moderately soft faecal with moistened loops 3: Dampness Large circular stool 4: Consistent stool with very large wetness circular loop For each test compound, Miller-Tainter's method (Pr
oc.Soc.Exp.Biol.Med. 57 , 261, 1944), the dose that causes diarrhea in 50% of the animals was evaluated. Compound, Example No. ED ₅₀ , mg / Kg 1 0.6 2 50 3 0.15 4 ＞ 100 5 ＞ 100 6 ＞ 100 7 10 8 1.7 9 3.5 10 1.2 11 5 12 5.5 Arecoline HBr 35 4. Body temperature lowering activity 6 hours fasted Male rats weighing 25 to 30 g (CD ₁ CHARLES RIVERS) were used. Body temperature was recorded by a thermocouple inserted about 15 cm into the rectum and connected to an electric thermometer. The test compounds were administered orally or subcutaneously, and body temperature values were measured at 0, 30, 60, 120 and 180 minutes after treatment.

The degree of hypothermia was evaluated as the difference between treated and control animals, and the dose required to reduce body temperature by 1 ° C was determined.

Next, the prolonging action of the test compound was evaluated by using a drug having an equivalent potency of lowering the body temperature by 1 to 1.5 ° C.

The results obtained are shown below.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Carla Bonettii Bergamo of Italy, Huontanella, Via Betucarino (no street number) (72) Inventor Emilio Toziya Milan of Italy, Via Plezzo, 80

Claims (10)

[Claims] 1. The following formula (I) [Wherein R is a hydrogen atom, a saturated or unsaturated linear, branched or cyclic alkyl group containing up to 8 carbon atoms, which is substituted with a free or esterified carboxyl group Or R is an aralkyl group containing up to 10 carbon atoms and R'is a saturated or unsaturated linear or branched alkyl group containing up to 8 carbon atoms. , Or --COalk ₁ or-(CH ₂ ) ₂ N (alk ₂ ) ₂ groups, wherein alk ₁ and alk ₂ represent an alkyl group containing up to 8 carbon atoms, Acid addition salt. 2. A first claim in which R represents a hydrogen atom.
A compound of formula (I) or an acid addition salt thereof according to the above item. 3. A compound of formula (I) or an acid addition salt thereof according to claim 1, wherein R represents a saturated or unsaturated alkyl group containing 1 to 4 carbon atoms. 4. A compound of formula (I) or an acid addition salt thereof according to claim 3, wherein R represents a methyl, ethyl, propyl or allyl group. 5. A compound of formula (I) or an acid addition salt thereof according to any one of claims 1 to 4, wherein R'represents a methyl group. 6. The compound having a compound name of 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime, 1-ethyl-1,2,5,6-tetrahydropyridine-3. -Carboxaldehyde-O-methyloxime, 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime, 1-propyl-1,2,5,6-tetrahydropyridine-3-
A carboxaldehyde-O-methyl oxime, 1-allyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyl oxime, according to claim 1. Compounds of formula (I) or their salts, especially the hydrochloride salt. 7. A compound of formula (I) according to claim 6 which is 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime hydrochloride. salts. 8. The following formula (I) [Wherein R is a hydrogen atom, a saturated or unsaturated linear, branched or cyclic alkyl group containing up to 8 carbon atoms, which is substituted with a free or esterified carboxyl group Or R is an aralkyl group containing up to 10 carbon atoms and R'is a saturated or unsaturated linear or branched alkyl group containing up to 8 carbon atoms. , Or --COalk ₁ or-(CH ₂ ) ₂ N (alk ₂ ) ₂ groups, wherein alk ₁ and alk ₂ represent an alkyl group containing up to 8 carbon atoms, A drug for treating Alzheimer's disease or senile dementia, which comprises, as an active ingredient, at least one pharmaceutically acceptable acid addition salt. 9. The following formula (I) [Wherein R is a hydrogen atom, a saturated or unsaturated linear, branched or cyclic alkyl group containing up to 8 carbon atoms, which is substituted with a free or esterified carboxyl group Or R is an aralkyl group containing up to 10 carbon atoms and R'is a saturated or unsaturated linear or branched alkyl group containing up to 8 carbon atoms. , Or --COalk ₁ or-(CH ₂ ) ₂ N (alk ₂ ) ₂ groups, wherein alk ₁ and alk ₂ represent alkyl groups containing up to 8 carbon atoms. The following equation (II) (Wherein R has the same meaning as described above) and one of its salts is represented by the formula (III) NH ₂ OR ′ ₁ (III) (wherein R ′ ₁ is a hydrogen atom, or Represents a saturated or unsaturated linear or branched alkyl group containing up to 4 carbon atoms) or one of its salts to give the corresponding formula (I _A ) Or a salt of this compound is formed, or
Or R ′ ₁ represents a hydrogen atom, the following formula (IV) R ′ ₂ Hal (IV) [wherein R ′ ₂ is —COalk ₁ or — (CH ₂ ) ₂ N- (alk ₂ ) ₂ group (here in alk ₁ and alk ₂ represent an have) defined above, the following formula Hal corresponds by the action of a compound of a halogen atom] (I _B) To give the compound, then the following formula (VI) R ₁ Hal optionally if R in the compound or compounds of formula (I _B) of the formula where R _'1 does not represent a hydrogen atom (I _A) represents a hydrogen atom (VI) [wherein Hal represents a halogen atom and R ₁ is a saturated or unsaturated linear, branched or cyclic alkyl group containing up to 8 carbon atoms (which is an esterified carboxyl group; May be substituted) or R ₁ is
Representing an aralkyl group containing up to 10 carbon atoms] by reacting a compound of formula (I _C ) (Where R ₁ and R ′ have the meanings given above), salting this compound if necessary, or
When R ₁ represents an esterified carboxyl group, the compound of formula (I _C ) is treated with a hydrolyzing agent to obtain a corresponding compound having a free carboxyl group, and this compound is subjected to salt formation if necessary. A process for preparing a compound of formula (I), characterized in that 10. The following formula (I) [Wherein R is a hydrogen atom, a saturated or unsaturated linear, branched or cyclic alkyl group containing up to 8 carbon atoms, which is substituted with a free or esterified carboxyl group Or R is an aralkyl group containing up to 10 carbon atoms and R'is a saturated or unsaturated linear or branched alkyl group containing up to 8 carbon atoms. , Or --COalk ₁ or-(CH ₂ ) ₂ N (alk ₂ ) ₂ groups, wherein alk ₁ and alk ₂ represent alkyl groups containing up to 8 carbon atoms. The following formula (V) (Wherein R'has the previously given meaning) a compound of formula (VI) R ₁ Hal (VI) [wherein Hal represents a halogen atom and R ₁ is saturated containing up to 8 carbon atoms] Or an unsaturated linear, branched or cyclic alkyl group (which may be substituted with an esterified carboxyl group), or R ₁ is
Representing an aralkyl group containing up to 10 carbon atoms] by reacting a compound of formula (VII) Of the compound of formula (I _C ) (Wherein R ₁ and R ′ have the meanings given above), salting this compound if desired or alkyl substituted with a carboxyl group on which R ₁ is esterified A group of the formula (I) which is characterized in that a hydrolyzing agent is applied to give a corresponding compound having a free carboxyl group, and this compound is salted if desired.
Of the compound of.